Pancreatic cancer, inflammation, and microbiome

Abstract

Pancreatic cancer is one of the most lethal cancers worldwide. No effective screening methods exist, and available treatment modalities do not effectively treat the disease. Inflammatory conditions such as pancreatitis represent a well-known risk factor for pancreatic cancer development. Yet only in the past 2 decades has pancreatic cancer been recognized as an inflammation-driven cancer, and the precise mechanisms underlying the pathogenic role of inflammation are beginning to be explored in detail. A substantial amount of preclinical and clinical evidence suggests that bacteria are likely to influence this process by activating immune receptors and perpetuating cancer-associated inflammation. The recent explosion of investigations of the human microbiome have highlighted how perturbations of commensal bacterial populations can promote inflammation and promote disease processes, including carcinogenesis. The elucidation of the interplay between inflammation and microbiome in the context of pancreatic carcinogenesis will provide novel targets for intervention to prevent and treat pancreatic cancer more efficiently. Further studies toward this direction are urgently needed.

Figure 1. Summary of the interplay between tumor-associated inflammation and microbiome, and their key roles in pancreatic carcinogenesis

Pancreatic cancer progresses through a series of defined stages that involve acinar-to-ductal metaplasia (ADM) in response to repetitive injury, development of pre-neoplastic lesions, and eventually invasive cancer. (1) Pancreatitis can be caused by genetic and environmental factors (e.g. alcohol), and can promote pancreatic carcinogenesis by inducing ADM while inhibiting OIS. (2) Noxious stimuli to the pancreas result in a low-grade maladaptive inflammatory response termed “parainflammation” that can synergize with mutant Kras in tumor development and evasion of OIS (3), and recruit immune cells that promote cancer-associated inflammation (4). Environmental factors, such as antibiotics and alcohol consumption, as well as pancreatitis can cause derangement of the gut microbiome and compromise the intestinal barrier function to promote translocation of bacteria to the pancreas (5). Translocated dysbiotic bacteria (pathobionts) can stimulate PRRs and inflammasomes and perpetuate tumor-associated inflammation. Treatment modalities such as chemotherapy and ratiotherapy can also influence the microbiome; alterations in the microbiome (dysbiosis) can have detrimental effects on the efficacy of chemotherapy and immunotherapy (6). CAF, cancer-associated fibroblasts; DC, dendritic cells; GIT, gastrointestinal tract; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; MDSC, myeloid-derived suppressor cells; OIS, oncogene-induced senescence; PanIN, pancreatic intraepithelial neoplasia; PRRs, pattern-recognition receptors; PSC, pancreatic stellate cells; TAM, tumor-associated macrophages.